The functional connectivity within primary visual cortex exhibits heightened sensitivity to visual experience during an interval late in development termed the critical period. Abnormal visual experience during the critical period is the cause of amblyopia, a prevalent childhood visual disorder. Treatment is most effective in children before the close of the critical period. Subsequently, plasticity diminishes and effective therapy is more difficult. In a mouse model of amblyopia, monocular deprivation during the critical period, but not thereafter, both shifts the relative responsiveness of neurons in visual cortex and decreases visual acuity. Analogous to clinical findings, these deficits persist if normal vision is restored after the close of the critical period. The nogo-66 receptor (NgR1) is required to close the critical period. In mice lacking NgR1, plasticity during the critical period is normal, but it continues such that adult mice display the same plasticity as during the critical period. This proposal investigates how NgR1 closes the critical period. Specific Aim 1 dissects where NgR1 expression is required with cortical circuitry to close the critical period and limit further OD plasticity with a combination of mouse genetics and electrophysiological recordings. Specific Aim 2 exploits the unique plasticity phenotype of NgR1 mutant mice to study how structural synaptic plasticity contributes to OD plasticity with repeated two-photon in vivo imaging. Specific Aim 3 explores whether blocking NgR1 function after the critical period will reactivate OD plasticity and improve visual acuity in amblyopic mice. The goal of this proposal is to improve understanding of how cortical plasticity is governed in the developing and mature visual system. PUBLIC HEALTH RELEVANCE: Abnormal vision during a sensitive or 'critical' period in childhood is the cause of amblyopia, also known as lazy eye. Treatment for amblyopia is most effective during the critical period. This research investigates how the critical period closes and explores how to 'reopen' the critical period in adults.